Oral 2-methyl-thieno-benzodiazepine formulation

ABSTRACT

The invention provides a pharmaceutically elegant solid oral formulation of olanzapine and a process for making such formulation.

FIELD OF THE INVENTION

[0001] This invention provides an improved pharmaceutically eleganttablet formulation of2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, hereinafter referred to as olanzapine, and processessfor the preparation thereof.

BACKGROUND OF THE INVENTION

[0002] The compound2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine compound has useful central nervous system activity.Certain tablet formulations of olanzapine are known, as described inU.S. Pat. No. 5,229,382. However, improved oral formulations weredesired in light of the moisture sensitive, polymorphic nature ofolanzapine, the tendency of olanzapine to undesirably discolor in theknown tablet formulation, and due to the surprisingly potent nature ofolanzapine.

SUMMARY OF THE INVENTION

[0003] The presently claimed invention provides a pharmaceuticallyelegant solid oral formulation for comprising olanzapine intimatelymixed with a bulking agent providing satisfactory hardness, friability,and disintegration time, binder, disintegrant, a dry binder to providefriability, and a lubricant; wherein such solid oral formulation iscoated with polymer selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose,sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid estercopolymer, ethylacrylate-methylmacracrylate copolymer, methylcellulose,and ethylcellulose.

[0004] A method for preparing pharmaceutically elegant, stable solidoral olanzapine formulations having a polymer coat selected from thegroup consisting of hydroxypropyl methyl cellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose,hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethylmethacrylatemethylacrylate acid ester copolymer,ethylacrylate-methylmacracrylate copolymer, methylcellulose, andethylcellulose, comprised of using a high shear aqueous wet granulationwith fluid bed drying process.

DETAILED DESCRIPTION OF THE INVENTION

[0005] Olanzapine, a potent compound having desired central nervoussystem activity has a tendency to undergo undesired polymorphictransformation, pharmaceutically undesired discoloration, and demandscare to assure homogeniety of the finished solid formulation.

[0006] Applicants have discovered that olanzapine undergoes undesirablediscoloration when contacted with certain excipients including powderblends. Further, the discoloration was exacerbated by ambient airconditions, at elevated temperatures, and by moist environments.Although the discoloration phenomenon does not produce in increase inthe number of total related substances, the browning and mottlingappearance is-not generally considered pharmaceutically acceptable forcommercial purposes.

[0007] Applicants have discovered that coating the solid oralformulation with a polymer selected from the group consisting ofhydroxypropyl methyl cellulose, hydroxyethyl cellulose,methylhydroxyethylcellulose, sodium carboxymethylcellulose,hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethylmethacrylatemethylacrylate acid ester copolymer,ethylacrylate-methylmacracrylate copolymer, methylcellulose, andethylcellulose as a coating or subcoating provides a uniform, physicalstability and effectively prevents the undesired discolorationphenomenon.

[0008] Most preferred polymer coats are hydroxypropyl methyl cellulose,hydroxypropylcellulose, methylcellulose, and ethylcellulose. Anespecially preferred polymer coat is hydroxypropyl methylcellulose.

[0009] Applicants have discovered that2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (olanzapine), which is a compound of the formula I:

[0010] exists as two anhydrous forms which are clearly distinguishableby x-ray powder diffractometry.

[0011] Unfortunately, anhydrous Form II olanzapine is metastable and istherefore not well suited for commercial use in pharmaceuticalformulations. Applicants have discovered that the pharmaceuticallyelegant anhydrous Form I olanzapine can be formulated in itssubstantially pure form as a stable solid oral preparation. Suchformulation provides assurance of a uniform pharmaceutically elegantproduct substantially free of Form II impurity in order to comply withregulatory requirements.

[0012] The Form I anhydrous2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is the most stable form of the compound; however,Applicants have discovered that the Form I anhydrous olanzapine issubject to undesired crystalline transformations in the presence ofcertain solvents. Further certain excipients exacerbate physicalinstability. For commercial pharmaceutical development and compliancewith regulatory guidelines, it is important to assure that marketedformulations comprise a uniform pharmaceutically elegant substantiallypure anyhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine compound as the active ingredient and most preferably theformulation is free from undesired discolorations.

[0013] The substantially pure crystalline anhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Form I) has a typical X-ray powder diffraction patternsubstantially as follows, using a Sieman's D5000 diffractometer equippedwith a copper radiation source, wherein d represents the interplanerspacing: d I/I₁ 10.2689 100.00 8.577 7.96 7.4721 1.41 7.125 6.50 6.14593.12 6.071 5.12 5.4849 0.52 5.2181 6.86 5.1251 2.47 4.9874 7.41 4.76654.03 4.7158 6.80 4.4787 14.72 4.3307 1.48 4.2294 23.19 4.141 11.283.9873 9.01 3.7206 14.04 3.5645 2.27 3.5366 4.85 3.3828 3.47 3.2516 1.253.134 0.81 3.0848 0.45 3.0638 1.34 3.0111 3.51 2.8739 0.79 2.8102 1.472.7217 0.20 2.6432 1.26 2.6007 0.77

[0014] Form II olanzapine (Form II) has a typical X-ray powderdiffraction pattern substantially as follows, using a Sieman's D5000diffractometer equipped with a copper radiation source, wherein drepresents the interplaner spacing: d I/I₁ 9.9463 100.00 8.5579 15.188.2445 1.96 6.8862 14.73 6.3787 4.25 6.2439 5.21 5.5895 1.10 5.3055 0.954.9815 6.14 4.8333 68.37 4.7255 21.88 4.6286 3.82 4.533 17.83 4.46245.02 4.2915 9.19 4.2346 18.88 4.0855 17.29 3.8254 6.49 3.7489 10.643.6983 14.65 3.5817 3.04 3.5064 9.23 3.3392 4.67 3.2806 1.96 3.2138 2.523.1118 4.81 3.0507 1.96 2.948 2.40 2.8172 2.89 2.7589 2.27 2.6597 1.862.6336 1.10 2.5956 1.73

[0015] The x-ray powder diffraction patterns set forth herein wereobtained with a copper K of wavelength=1.541 A. The interplanar spacingsin the column marked “d” are in Angstroms. The typical relativeintensities are in the column marked “I/I₁”. The detector was a Kevexsilicon lithium solid state detector.

[0016] As used herein “substantially pure” shall refer to anhydrous FormI associated with <5% Form II; and most preferably it shall refer to <2%Form II. It is further preferred that “substantially pure” shall referto <0.5% non-Form I polymorph.

[0017] As used herein “substantially pure” shall refer to anhydrous FormI associated with about <5% Form II; and most preferably it shall referto about <2% Form II. It is further preferred that “substantially pure”shall refer to < 0.5% related substances. When the Form I polymorph isformulated as a pharmaceutical composition, “substantially pure” shallpreferably refer to about <15% Form II polymorph; more preferably, theterm shall refer to about <10% Form II polymorph when the Form Ipolymorph is formulated as a pharmaceutical, and it is especiallypreferred that the term shall refer to about <5% Form II polymorph whenthe substantially pure substance is formulated.

[0018] As used herein, the term“2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine”refers to a technical grade of2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepinewhen no specific solvate or polymorph is named. Typically, the technicalgrade olanzapine contains less than about 5% undesired relatedsubstances and may be a mixed polymorph. Such technical grade olanzapinemay contain less than about 1% undesired related substances.

[0019] The term “crude” refers to a form of olanzapine typicallyassociated with undesired polymorph and/or greater than about 5%undesired related substances. Such crude grade olanzapine may containless than about 1% undesired related substances.

[0020] As used herein, the term “mammal” shall refer to the Mammaliaclass of higher vertebrates. The term “mammal” includes, but is notlimited to, a human. The term “treating” as used herein includesprophylaxis of the named condition or amelioration or elimination of thecondition once it has been established.

[0021] The anhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepinecompound is effective over a wide dosage range, the actual doseadministered being dependent on the condition being treated. Forexample, in the treatment of adult humans, dosages of from about 0.25 to50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg perday may be used. A once a day dosage is normally sufficient, althoughdivided doses may be administered. For treatment of central nervoussystem disorders, a dose range of from 1 to 30 mg, preferably 1 to 20 mgper day is suitable. Radiolabelled Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine, can be detected in the saliva and thus the compoundcan potentially be monitored in patients to assess compliance.

[0022] The Form I olanzapine compound is the most stable known form ofolanzapine and is therefore important for the commercial development ofpharmaceutical formulations which will comply with regulatoryguidelines. The Form I olanzapine compound may form an undesired crystalform in the presence of certain solvents and excipients, therefore, inmaking the compositions of the invention it is most desired to preparethe formulation using a method which does not require dissolution of theolanzapine substance. The Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine compound can be converted to the less desirablepolymorphic forms by contact with methylene chloride, for example.Additionally, for example, polyethylene glycol contact with theolanzapine substance produces undesired discoloration, particularlyunder moist conditions.

[0023] Applicants believe that a dry blend direct compression process ordry granulated processes for preparing solid oral formulations creategreater opportunity for undesired poor dose uniformity. In light of thepotent nature of olanzapine, consistent dose uniformity is imperitive.In accordance with this invention, Applicants have discovered that ahigh shear aqueous wet granulation with fluid bed drying is the mosteffective method for preparing pharmaceutically elegant, stable,olanzapine oral formulations.

[0024] Uncoated tablets stored at ambient conditions (approximately 23°C. and 40% relative humidity) in amber, high density polyethylenebottles do not show signs of discoloration after 24 months; however, ifthe bottle is opened such that the tablets are exposed to open airambient conditions then discoloration occurs within 5 days.

[0025] Applicants attempted to film coat the tablet surface to provide amore pharmaceutically elegant solid oral formulation. Groups of tabletscontaining 5 mg of olanzapine were coated with a clear coat(hydroxypropyl methylcellulose with polyethylene glycol), a white coat(a dry blend of ingredients comprising hydroxypropyl methyl cellulose,polyethylene glycol, polysorbate 80 and titanium dioxide dispersed inwater and used an an aqueous dispersion to film coat the formulation),and a white coat with a clear coat subcoating. The coated tablets wereplace in bottles and stored at 40° C./75% relative humidity (RH) and 60°C. Visual evaluations indicated that the subcoated plus white coatedtablets inhibited discoloration the longest period of time; however, thecoated tablet characterization work indicated the the tablet coatingsdid not provide an acceptable solution to the discoloration problem.

[0026] The coating characterization work demonstrated that the tabletcoating provided a surface barrier from air/oxygen mediateddiscoloration; however, the coating exacerbated the moisture relatedsurface changes. As a result, coated tablets stored under open dishambient conditions at low humidity showed no discoloration over extendedperiods of time while coated tablets stored at ambient conditions and85% relative humidity mottled severely. Further evaluation showed thatthe moisture related discoloration was due to the presence of theplasticizer polyethylene glycol in the subcoating formula.

[0027] A new solid oral formulation was prepared that used ahydroxypropropyl methylcellulose subcoating and a white color coating.The new formulation did not discolor after 90 days of open dish storageat 40° C., 60° C., 40° C./75% RH, ambient temperature with 75% RH, or atambient temperature with 85% RH. The hydroxypropyl methylcellulosecoating which is free of polyethylene glycol is critical to ensure thatdiscoloration does not occur on the tablet surface. It provides aneffective barrier between the white color coat which provides anacceptable medium for imprinting and color dressing of the product. Thehydroxypropylmethylcellulose coating provides sufficient barrier toprevent discoloration attributable to the polyethylene glycol in thewhite color coat. Alternative white film coat formulas containingalternative plasticizers were evaluated; however, none were able toprevent discoloration in all test conditions after 90 days of storage.Therefore, the hydroxypropyl methylcellulose coat or subcoating is asurprising and critical component of pharmaceutically elegant solid oralformulations of olanzapine.

[0028] A diluent or bulking agent should be selected to provide anincrease in tablet size. One especially preferred diluent is lactose.Various forms of lactose are appropriate for such formulations includinganhydrous, hydrous, and spray dried forms. The most desired form oflactose can be selected based on desired dissolution, contentuniformity, hardness, friability, and disintegration time.

[0029] The formulation should include a binder for use in thegranulation step. The artisan can choose an appropriate binder based onthe acceptable viscosity, and desired hydration. Hydroxypropyl celluloseis especially preferred for use as a binder in the granulation step. Thehydroxypropyl cellulose may vary in particle size. Fine gradehydroxypropyl cellulose is especially preferred for most claimedformulations.

[0030] The desired formulation includes a disintegrant for use in thegranulation as well as in the running powders to facilitate thedisintegration process. There are a variety of grades available, and thegrade may be selected based on the acceptable batch variability. Aparticularly preferred disintegrant is crospovidone. A fine grade ofcrospovidone provides particularly desirable consistency betweenbatches.

[0031] The artisan may choose appropriate dry binders using knownmethods. Such binders should be selected to assure that satisfactoryfriability is attained. Most preferably, dry binder is microcrystallinecellulose; however, other appropriate dry binders may be selected. Suchmicrocrystalline cellulose may be in a granular form.

[0032] The artisan can choose an appropriate lubricant to preventsticking and picking of the tablets to the compression tooling. Onepreferred lubricant is magnesium stearate.

[0033] The artisan can readily choose other appropriate aqueousdispersion film coats (color mix) for application over the hydroxypropylmethylcellulose layer. Typically, the color mixture is a dry blend ofingredients which may be dispersed in water and used as an aqueousdispersion to film coat solid formulations. One example of a typicalcolor mixture is comprised of hydroxypropyl methylcellulose,polyethylene glycol, polysorbate 80, and titanium dioxide.

[0034] A variety of edible inks known to the artisan are appropriate forimprinting the finished formulation. For example, one typical edible inkis comprised of shellac, ehtyl alcohol, isopropyl alcohol, n-butylalcohol, propylene glycol, ammonium hydroxide, and FD&C Blue.

[0035] The solid formulation is most preferably subcoated withhydroxypropyl methylcellulose, coated with a color coat, and imprintedwith an edible ink. The solid formulation may be polished using standardmethods such as carnauba wax polishing, if desired.

[0036] A preferred formulation of the invention is a solid oralformulation comprising from about 1 to about 20 mg or 1 to 10 mg ofactive anhydrous Form I olanzapine as an effective amount of the activeingredient, provided that such solid oral formulation is coated withpropyl methyl.

[0037] Most preferably, the solid oral formulation is contained inpackaging materials which protect the formulation from moisture andlight. For example, suitable packaging materials include amber coloredhigh density polyethylene bottles, amber colored glass bottles, andother containers made of a material which inhibits the passage of light.Most preferably, the packaging will include a desiccant pack. Thecontainer may be sealed with an aluminum foil blister to provide thedesired protection and maintain product stability.

[0038] A study of the hydroxypropyl methylcellulose sub-coated tabletsin an amber colored bottle having a desiccant pack stored at harsh, 40°C./75% RH conditions for six months showed pharmaceutically acceptablestability with a 0.4% to about 1.2% increase in total relatedsubstances.

[0039] The materials for the present invention can be purchased orprepared by a variety of procedures well known to those of ordinaryskill in the art. The olanzapine compound can be prepared as describedby Chakrabarti in U.S. Pat. No. 5,229,382 ('382), herein incorporated byreference in its entirety. It is most desirable to prepare a rapidlydissolving formulation comprising substantially pure crystalline Form Iolanzapine. Such substantially pure crystalline Form I olanzapine may beprepared using the techniques described herein by the Preparationsection herein infra.

[0040] As used herein mixing steps may be accomplished using commonagitation methods such as stirring, shaking, and the like. As usedherein the phrase “producing crystalline product from the mixture” shallrefer to crystallization from the stated mixture of compound andsolvent. Further, the artisan recognizes that crystallization processesmay include seeding, chilling, scratching the glass of the reactionvessel, and other such common techniques.

[0041] Compound characterization methods include, for example, x-raypowder pattern analysis, thermogravimetric analysis (TGA), differentialscanning calorimetery (DSC), titrametric analysis for water, and H¹-NMRanalysis for solvent content.

[0042] The formulations were studied to assure that the Form I polymorphwas substantially pure using ¹³C Cross polarization/magic angle spinning(CP/MAS) NMR. Spectra were obtained using a Varian Unity 400 MHzspectrometer operating at a carbon frequency of 100.577 MHz and equippedwith a complete solids accessory and Varian 5 mm or 7 mm VT CP/MASprobes. Measurement conditions were optimized for Olanzapine Form I andwere as follows: 90° proton r.f. pulse 4.5 ms, contact time 1.1 ms,pulse repetition time 5 s, MAS frequency 7.0 kHz, spectral width 50 kHz,and acquisition time 50 ms. Chemical shifts were referenced to the CH₃of hexamethylbenzene (d=17.3 ppm) by sample replacement. It wasdetermined that the substantially pure Form I polymorph is retainedthroughout the formulation process claimed herein. Therefore, theformulations of this invention provide substantially pure Form Iolanzapine polymorph in a pharmaceutically elegant formulation withoutproducing undesired polymorphic transformation.

[0043] The following examples are provided for purposes of illustrationand are not to be construed as limiting the scope of the claimedinvention.

Preparation 1 Crystalline Form II olanzapine

[0044] A 10 gram sample of crude2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in methylene chloride (100) gm and stirredat ambient temperature (20-25° C.) for a period of 1 hour. The slurrywas vacuum filtered and the filtrate was recovered. The stirred filtratewas chilled to 0-5° C. in an ice bath and the solvent was slowlyevaporated under a stream of nitrogen to a thick paste. Approximately ¾of the solvent was removed by evaporation. A quantity of prechilledmethylene chloride (30 gm, 0-5° C.) was mixed into the thick paste. Theresulting slurry was vacuum filtered and allowed to air dry on thefilter. The isolated solid was further dried in a vacuum oven at 50° C.for a period of 30 minutes. Isolated: 4.8 gm. X-ray powdercharacterization: Form II+CH₂Cl₂ Solvate.

[0045] The isolated solid was redried in a vacuum oven at 50° C. under astream of nitrogen for a period of 30 hours. Isolated: 4.5 gm X-raypowder characterization: Form II. (described supra.)

Preparation 2 Form I olanzapine

[0046] A sample of ethyl acetate which was saturated with technicalgrade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[ 2,3-b][1,5]benzodiazepine was contacted with Form II2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (0.3 g), a seed of anhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine and stirred at about 25° C. for about 5 hours. Thereaction product was isolated by vacuum filtration and dried underambient conditions. Yield: 0.25 g. X-ray powder analysis indicated thatthe product was anhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

Preparation 3 Technical Grade olanzapine

[0047]

[0048] In a suitable three neck flask the following was added:Dimethylsulfoxide (analytical) 6 volumes Intermediate 1 75 gN-Methylpiperazine (reagent) 6 equivalents

[0049] Intermediate 1 can be prepared using methods known to the skilledartisan. For example, the preparation of the Intermediate 1 is taught inthe '382 patent.

[0050] A sub-surface nitrogen sparge line was added to remove theammonia formed during the reaction. The reaction was heated to 120° C.and maintained throughout the duration of the reaction. The reactionswere followed by HPLC until •5% of the intermediate 1 was leftunreacted. After the reaction was complete, the mixture was allowed tocool slowly to 20° C. (about 2 hours). Each reaction mixture was thentransferred to an appropriate three neck round bottom flask and waterbath. To this solution with agitation was added 10 volumes reagent grademethanol and the reaction was stirred at 20° C. for 30 minutes. Threevolumes of water was added slowly over about 30 minutes. The reactionslurry was cooled to zero to 5° C. and stirred for 30 minutes. Theproduct was filtered and the wet cake was washed with chilled methanol.The wet cake was dried in vacuo at 45° C. overnight. The product wasidentified as technical olanzapine.

[0051] Yield: 76.7%; Potency: 98.1%

[0052] The procedure of Preparation 3 was repeated substantially asdescribed above and provided a yield of 81% with a potency of 101.1%.

Preparation 4 Technical Grade olanzapine

[0053] Intermediate 1 (supra) was suspended in DMSO (3.2 vol.) andtoluene (4.5 vol.). A portion (•0.65 vol.) of the solvent was removed bydistillation at 120-125° C. The mixture was cooled to 110° C.,N-methylpiperazine(NMP, 4.2 equiv.) was added and the mixture heatedback to reflux (120-125° C.). Another portion (•1 vol.) of the solventwas removed by distillation to dry the reaction mixture. A vigorousreflux was desired to drive the reaction to completion (about 7 hrs.) byremoving ammonia from the reaction. The product was isolated by the slowaddition of water (12.75 vol.) to the cooled (10° C.) reaction solution.The product was collected by filtration and washed with chilled water (2vol.). The crude olanzapine was dried in vacuo at 60° C. The product wasrecrystallized from hot toluene (5 vol.) to give a technical gradeolanzapine. After drying in vacuo at 50° C., the technical gradeolanzapine was recrystallized again from ethyl acetate (10 vol.)/toluene(0.62 vol.)/methanol (3.1 vol.)to give olanzapine as a methanol solvate.The methanol solvate upon drying at >50° C. was converted to ananhydrous technical grade olanzapine.

Preparation 5 Form I from acetone

[0054] A 3.0 g sample of technical grade2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in acetone (30 g). The mixture was stirredand heated to about 60° C. The mixture was maintained at about 60° C.for about 30 minutes. The mixture was allowed to cool to about 25° C.The resulting product was isolated using vacuum filtration. The productwas identified as Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine using x-ray powder analysis. Yield: 0.8 g.

Preparation 6 Form I using tetrahydrofuran

[0055] An 8.0 g sample of technical grade2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in tetrahydrofuran (25 g). The mixture wasstirred and heated to about 60° C. The mixture was maintained at about60° C. for about 30 minutes. The mixture was allowed to cool to about25° C. The resulting product was isolated using vacuum filtration. Theproduct was identified as Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine using x-ray powder analysis. Yield: 1.3 g.

Preparation 7 Form I using ethyl acetate

[0056] A 270 g sample of technical grade2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in ethyl acetate (2.7 L). The mixture washeated to about 76° C. and maintained at about 76° C. for about 30minutes. The mixture was allowed to cool to about 25° C. The resultingproduct was isolated using vacuum filtration. The product was identifiedas Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine using x-ray powder analysis.

[0057] Yield: 197 g.

Preparation 8 Form I from t-butanol

[0058] A 1.0 g sample of technical grade2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in tert-butanol (30 g). The stirred mixturewas heated to about 60° C. and maintained at about 60° C. for about 30minutes. The mixture was allowed to cool to about 25° C. The resultingproduct was isolated using vacuum filtration. The product was identifiedas Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine using x-ray powder analysis.

[0059] Yield: 0.3 g.

Preparation 9 Form I from Slurry Conversion of Form II in Toluene

[0060] A 0.5 g sample of technical grade2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepineand a 0.5 g sample of Form II2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepinewere suspended in toluene (5 ml), presaturated with2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.The mixture was stirred in a sealed vial at about ambient temperaturefor about 22 hours. The resulting product was isolated using vacuumfiltration and dried under vacuum at about 45° C. The product wasidentified as Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepineusing x-ray powder analysis.

EXAMPLE 1

[0061] A portion of the hydroxypropyl cellulose was dissolved inpurified water to form a solution for granulation. The remaininghydroxypropyl cellulose (total of 4.0% w/w final tablet weight), whichwas an extra fine grade, was combined with the olanzapine (1.18% w/w),lactose (79.32% w/w) and a portion of the crospovidone (5% w/w) in ahigh shear granulator. All ingredients were security sieved prior toaddition and dry blended in the granulator. This mixture was thengranulated with the hydroxypropyl cellulose solution in the high sheargranulator. The granulation was wet sized using standard methods. Thewet granulation was then dried in a fluidized bed dryer and sized. Thematerial was then added to a tumble bin mixer.

[0062] The running powders consisting of microcrystalline cellulose(granular) (10% w/w), magnesium stearate (0.5% w/w), and the remainderof the crospovidone were added to the sized granulation. The mixture wasblended and compressed with the appropriate tooling on tabletcompression equipment.

[0063] Subcoating

[0064] Hydroxypropyl methylcellulose (10% w/w) was mixed with purifiedwater to form a solution. Core tablets were divided into approximatelyequal sections and spray coated with the hydroxypropyl methylcellulosesolution . The operation was performed in a perforated coating pan.

[0065] Coating of Core Tablets

[0066] Color Mixture White (hydroxypropyl methylcellulose, polyethyleneglycol, polysorbate 80, and titanium dioxide) was mixed with purifiedwater to form the coating suspension. Subcoated tablets were dividedinto approximately equal sections and spray coated with the coatingsuspension described above. The operation was performed in a perforatedcoating pan.

[0067] The coated tablets were lightly dusted with carnauba wax andimprinted with appropriate identification.

EXAMPLE 2

[0068] The process substantially as described above in Example 1 wasrepeated using the following ingredients to provide pharmaceuticallyelegant tablet formulations containing 1, 2.5, 5, 7.5, and 10 mgolanzapine, respectively, per tablet:

[0069] 1 mg olanzapine per tablet: Quantity Names of Ingredients(mg/tablet) Active Ingredient Olanzapine 1.0 Other Ingredients Lactose67.43 Hydroxypropyl 3.40 Cellulose Crospovidone 4.25 Microcrystalline8.50 Cellulose Magnesium Stearate 0.42 Subcoating Hydroxypropyl 1.70Methylcellulose Coating Color Mixture White 3.47 Polishing Carnauba Waxtrace Imprinting Edible Blue Ink trace

[0070] Olanzapine 2.5 mg Tablets Quantity Names of Ingredients(mg/tablet) Active Ingredient Olanzapine 2.5 Other Ingredients Lactose102.15 Hydroxypropyl 5.20 Cellulose Crospovidone 6.50 Microcrystalline13.00 Cellulose Magnesium Stearate 0.65 Subcoating Hydroxypropyl 2.60Methylcellulose Coating Color Mixture White 5.30 Polishing Carnauba Waxtrace Imprinting Edible Blue Ink trace

[0071] Olanzapine 5.0 mg Tablets Quantity Names of Ingredients(mg/tablet) Active Ingredient Olanzapine 5.00 Other Ingredients Lactose156.00 Hydroxypropyl 8.00 Cellulose Crospovidone 10.00 Microcrystalline20.00 Cellulose Magnesium Stearate 1.00 Subcoating Hydroxypropyl 4.00Methylcellulose Coating Color Mixture White 8.16 Polishing Carnauba Waxtrace Imprinting Edible Blue Ink trace

[0072] Olanzapine 7.5 mg Tablets Quanitity Names of Ingredients(mg/tablet) Active Ingredient Olanzapine 7.50 Other Ingredients Lactose234.00 Hydroxypropyl 12.00 Cellulose Crospovidone 15.00 Microcrystalline30.00 Cellulose Magnesium Stearate 1.50 Subcoating Hydroxypropyl 6.00Methylcellulose Coating Color Mixture White 12.24 Polishing Carnauba Waxtrace Imprinting Edible Blue Ink trace

[0073] Olanzapine 10.0 mg Tablets Quantity Names of Ingredients(mg/tablet) Active Ingredient Olanzapine 10.00 Other Ingredients Lactose312.00 Hydroxypropyl 16.00 Cellulose Crospovidone 20.00 Microcrystalline40.00 Cellulose Magnesium Stearate 2.00 Subcoating Hydroxypropyl 8.00Methylcellulose Coating Color Mixture White 16.32 Polishing Carnauba Waxtrace Imprinting Edible Blue Ink trace

We claim:
 1. A method for preparing a stable pharmaceutically elegantsolid oral formulation of olanzapine having a polymer coating selectedfrom the group consisting of hydroxypropyl methyl cellulose,hydroxyethyl cellulose, methylhydroxyethylcellulose, sodiumcarboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone,dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer,ethylacrylate-methylmacracrylate copolymer, methylcellulose, andethylcellulose, comprised of using a high shear aqueous wet granualtionwith fluid bed drying.
 2. A method of claim 1 wherein olanzapine issubstantially pure anhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-1H-thieno[2,3-b][1,5] benzodiazepinehaving a typical X-ray powder diffraction pattern substantially asfollows, using a Sieman's D5000 diffractometer wherein d represents theinterplaner spacing: d 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.48495.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.98733.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.87392.8102 2.7217 2.6432 2.6007.


3. A method of claim 2 wherein the polymer coat is selected from thegroup consisting of hydroxypropyl methyl cellulose,hydroxypropylcellulose, methylcellulose, and ethylcellulose.
 4. A methodof claim 3 wherein the polymer coat is hydroxypropylmethyl cellulose. 5.A solid oral formulation comprising olanzapine intimately mixed with abulking agent providing satisfactory hardness, friability, anddisintegration time, binder, disintegrant, a dry binder to assureadequate minimize friability, and a lubricant; wherein such solid oralformulation is coated with a polymer selected from the group cosistingof hydroxypropyl methyl cellulose, hydroxyethyl cellulose,methylhydroxyethylcellulose, sodium carboxymethylcellulose,hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethylmethacrylatemethylacrylate acid ester copolymer,ethylacrylate-methylmacracrylate copolymer, methylcellulose, andethylcellulose.
 6. A formulation of claim 5 wherein the polymer coat isselected from the group consisting of hydroxypropyl methyl cellulose,hydroxypropylcellulose, methylcellulose, and ethylcellulose.
 7. Aformulation of claim 6 wherein the polymer coat is hydroxypropylmethylcellulose.
 8. A formulation of claim 7 wherein the bulking agent islactose.
 9. A formulation of claim 8 wherein the form of lactose isselected from the group consisting of hydrous, anhydrous, and spraydried forms of lactose.
 10. A formulation of claim 8 wherein the binderis hydroxypropyl cellulose and the disintegrant is crospovidone.
 11. Aformulation of claim 10 wherein the dry binder is microcrystallinecellulose.
 12. A formulation of claim 11 wherein the lubricant ismagnesium stearate.
 13. A formulation of claim 7 wherein thehydroxypropyl methylcellulose is a subcoating which is further coatedwith a aqueous dispersion film coat.
 14. A formulation of claim 12wherein the solid formulation is imprinted using an edible ink.
 15. Aformulation of claim 12 wherein the formulation comprises from about 1to about 3% w/w olanzapine; from about 69.5 to about 87.5% w/w lactose;from about 3.5 to about 4.5% w/w hydroxypropyl cellulose; from about 4to about 6% w/w crospovidone; from about 9 to about 11% w/wmicrocrystalline cellulose; and from about 0.25 to about 1% magnesiumstearate.
 16. A formulation of claim 5 wherein the hydroxypropylmethylcellulose coating is from about 1.25 to about 3.5% w/w.
 17. Aformulation of claim 13 wherein the aqueous dispersible film is fromabout 3 to about 7% w/w.
 18. A formulation of claim 15 wherein the solidformulation is a tablet.
 19. A formulation of claim 18 wherein eachtablet provides a dose of olanzapine selected from the group consistingof 1, 2.5, 5, 7.5, 10, 15, and 20 mg.
 20. A formulation of claim 5wherein olanzapine is substantially pure anhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine having a typical X-ray powder diffraction patternsubstantially as follows, using a Sieman's D5000 diffractometer whereind represents the interplaner spacing: d 10.2689 8.577 7.4721 7.1256.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.33074.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.08483.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007.


21. A formulation of claim 14 wherein olanzapine is substantially pureanhydrous Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine having a typical X-ray powder diffraction patternsubstantially as follows, using a Sieman's D5000 diffractometer whereind represents the interplaner spacing: d 10.2689 8.577 7.4721 7.1256.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.33074.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.08483.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007


22. A formulation of claim 21 wherein substantially pure shall refer to≦2% Form II2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b]-[1,5]benzodiazepinewherein Form II has a typical X-ray powder diffraction patternsubstantially as follows, using a Sieman's D5000 diffractometer whereind represents the interplaner spacing: d 9.9463 8.5579 8.2445 6.88626.3787 6.2439 5.5895 5.3055 4.9815 4.8333 4.7255 4.6286 4.533 4.46244.2915 4.2346 4.0855 3.8254 3.7489 3.6983 3.5817 3.5064 3.3392 3.28063.2138 3.1118 3.0507 2.948 2.8172 2.7589 2.6597 2.6336 2.5956


24. A solid oral formulation comprising olanzapine, wherein theformulation is coated with a polymer selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodiumcarboxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone,dimethylaminoethyl methacrylate, methyl acrylate acid ester copolymer,ethyl acrylate-methyl methacrylate copolymer, methyl cellulose, andethyl cellulose and wherein the polymer coat does not containpolyethylene glycol.
 25. The formulation of claim 24 wherein the polymeris hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, or ethyl cellulose.
 26. The formulation of claim 24 whereinthe polymer is hydroxypropylmethyl cellulose.
 27. The formulation ofclaim 24 wherein the olanzapine is substantially in the form of the FormII polymorph.
 28. The formulation of claim 24 wherein the bulking agentin the formulation is lactose.
 29. The formulation of claim 24 whereinthe binder in the formulation is hydroxypropyl cellulose and thedisintegrant is crospovidone.
 30. The formulation of claim 24 whereinthe dry binder in the formulation is microcrystalline cellulose.
 31. Theformulation of claim 24 wherein the lubricant in the formulation ismagnesium stearate.
 32. The formulation of claim 26 wherein thehydroxypropyl methylcellulose coating is further coated with an aqueousdispersion film coat.
 33. The formulation of claim 32 wherein the solidformulation is imprinted using an edible ink.
 34. The formulation ofclaim 32 wherein the formulation comprises from about 1 to about 3% w/wolanzapine; from about 69.5 to about 87.5% w/w lactose; from about 3.5to about 4.5% w/w hydroxypropyl cellulose; from about 4 to about 6% w/wcrospovidone; from about 9 to about 11% w/w microcrystalline cellulose;and from about 0.25 to about 1% magnesium stearate.
 35. The formulationof claim 24 wherein the solid formulation is a table.
 36. Theformulation of claim 35 wherein each tablet provides a 1, 2.5, 5, 7.5,10, 15, or 20 mg dose of olanzapine.
 37. The formulation of claim 24wherein the solid formulation is in the form of granules.
 38. Theformulation wherein the formulation of claim 24 is for use in treating acondition selected from psychosis, schizophrenia, a schizophriformdisorder, mild anxiety, a gastrointestinal disorder, and acute mania.